Induction of drug-metabolizing enzymes is one of the mechanisms for drug-drug interaction. In general, the induction of the enzyme is caused by the increase of transcription of a drug-metabolizing enzyme gene, and in order to evaluate induction of the enzyme, screening is performed by using a recombinant reporter vector prepared by incorporating a part of a regulatory region of a drug-metabolizing enzyme gene into a 5′ upstream region of a reporter gene.
Cytochrome P450 (CYP), a major drug-metabolizing enzyme, consists of a gene superfamily, and there are many isozymes with different substrate specificities (Non-patent document 1). Among them, the CYP1A family is involved not only in metabolism of drug but also in metabolic activation of carcinogens such as polycyclic hydrocarbons and aromatic amines.
It is known that human CYP1A1 and CYP1A2 genes adjacently exist on the chromosome 15 in reverse directions (Non-patent document 2). For CYP1A1, a region which is responsible for the induction thereof by a drug is well-characterized (Non-patent document 3), and reporter systems that enable the evaluation of the induction by a drug have also been constructed (Non-patent documents 4 to 6). However, for CYP1A2, although it is known that the proximal region of the CYP1A2 gene is not enough for the induction thereof (Non-patent document 7), and it is not specified which regions are involved in the induction of CYP1A2.
Non-patent document 1: Pharmacogenetics, 6:1-42 (1996)
Non-patent document 2: Pharmacogenetics, 11:1-6 (2001)
Non-patent document 3: Ann. Rev. Pharmacol. Toxicol., 39:103-125 (1999)
Non-patent document 4: Toxicol. Appl. Pharmacol., 118:255-262 (1993)
Non-patent document 5: Fundam. Appl. Toxicol., 30:194-203 (1996)
Non-patent document 6: Drug Metab. Dispos., 33:312-320 (2005)
Non-patent document 7: Pharmacogenetics, 5:259-274 (1995)